MAST-CELLS EXPRESS A PERIPHERAL CANNABINOID RECEPTOR WITH DIFFERENTIAL SENSITIVITY TO ANANDAMIDE AND PALMITOYLETHANOLAMIDE

Mast cells are multifunctional bone marrow-derived cells found in muco sal and connective tissues and in the nervous system, where they play important roles in tissue inflammation and in neuroimmune interactions . Very little is known about endogenous molecules and mechanisms capab le of modulating mast cell activation. Palmitoylethanolamide, found in peripheral tissues, has been proposed to behave as a local autacoid c apable of downregulating mast cell activation and inflammation. A cogn ate N-acylamide, anandamide, the ethanolamide of arachidonic acid, occ urs in brain and is a candidate endogenous agonist for the central can nabinoid receptor (CB1). As a second cannabinoid receptor (CB2) has be en found in peripheral tissues, the possible presence of CB2 receptors on mast cells and their interaction with N-acylamides was investigate d. Here we report that mast cells express both the gene and a function al CB2 receptor protein with negative regulatory effects on mast cell activation. Although both palmitoylethanolalmide and anandamide bind t o the CB2 receptor, only the former downmodulates mast cell activation in vitro. Further, the functional effect of palmitoylethanolamide, as well as that of the active cannabinoids, was efficiently antagonized by anandamide. The results suggest that (i) peripheral cannahinoid CB2 receptors control, upon agonist binding, mast cell activation and the refore inflammation; (ii) palmitoylethanolamide, unlike anandamide, be haves as an endogenous agonist for the CB2 receptor on mast cells; (ii i) modulatory activities on mast cells exerted by the naturally occurr ing molecule strengthen a proposed autacoid local inflammation antagon ism (ALIA) mechanism; and (iv) palmitoylethanolamide and its derivativ es may provide antiinflammatory therapeutic strategies specifically ta rgeted to mast cells (''ALIAmides'').